Biomaterials for MEMS

152 G. Voskerician

7.3.2 Tissue Biocompatibility and Effect on Biofunctionality

Inflammation, wound healing, foreign body response, and fibrosis are recognized

as principal phases of the tissue or cellular host response to injury, here, as a result

of BioMEMS implantation (Fig. 7.1).

31,32

Inflammation represents the reaction of

the vascularized living tissue to the local injury created at the time of implantation.

The subsequent onset of wound healing leads to the formation of the granulation

tissue, characterized by angiogenesis and presence of fibroblasts (Fig. 7.2).

13

Fi-

nally, the foreign body reaction, represented by macrophages and foreign body

giant cells (FBGC), follows leading to fibrosis and fibrous encapsulation. The

fibrous tissue encapsulates the BioMEMS, isolating the implant from the local

tissue environment.

12,13

The size, shape, length of time of intended use, chemical

and physical properties of the BioMEMS drug delivery systems may be responsible

for variations in the intensity and duration of the inflammatory and/or wound-

healing process.

33−36

The inflammation and wound healing response can be divided into several

fundamental stages: acute inflammation, chronic inflammation, formation of gran-

ulation tissue, foreign body reaction, and fibrous capsule development (Fig. 7.1).

13

The acute phase of the inflammatory response occurs immediately after tissue

injury, and is of relatively short duration, lasting from minutes to days, depending

on the extent of the injury. It is characterized by plasma protein adsorption and the

migration of leukocytes from the microcirculation, including poly-morphonuclear

Figure 7.1. The host response to injury. The injury and the presence of the implanted

device jointly induce an inflammatory and wound healing response, characterized by the

following phases: acute inflammation, chronic inflammation, granulation tissue and fibrous

capsule formation. During this process, macrophages and foreign body giant cells undergo

“frustrated phagocytosis” in an attempt to breakdown the device.

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Application of MEMS in Drug Delivery 153

Figure 7.2. The temporal modulation of the cellularity present in the various stages of the

inflammatory and wound healing response. The intensity and time variables are dependent

upon the extent of the injury created by implantation and the size, shape, topography, and

chemical/physical properties of the device.

leukocytes (PMN), monocytes, and lymphocytes (Fig. 7.2). These inflammatory

cells actively migrate from the vasculature in response to chemotactic factors

present at the implant site. Protein-rich fluid (exudate) accompanies this cellular

movement. Further, increased vascular permeability facilitates this movement

resulting in accumulation of cells and exudate, and it is the result of several mech-

anisms including endothelial contraction, cytoskeletal reorganization, leukocyte-

mediated endothelial cell injury and leakage from regenerated capillaries.

13

Along

with the device itself, the extent of tissue injury proportionally contributes to the

overall extent of the inflammatory response. Placement is also critical, as more

destruction/injury of tissue in general leads to a more active acute inflammatory

phase.

The predominant cell type within the exudate during the acute phase is the

poly-morphonuclear leukocyte (PMN), also called a neutrophil. Its major role is

to attack and digest (phagocytose) bacteria, tissue debris and the foreign material,

so that wound healing can proceed.

37−39

. Although BioMEMS are not generally

phagocytosed by PMNs or macrophages due to the disparity in size, certain events

in phagocytosis are known to occur. While the implant size may prevent its total

ingestion by macrophages, they will attach to the device and undergo what is

termed “frustrated phagocytosis”.

13

This process does not involve engulfment

of the BioMEMS, but does cause the extracellular release of leukocyte products

(lysosomal enzymes, proteases and free radicals) in an attempt to degrade the

surface contact material (Fig. 7.3).

13

In general, the number of PMNs throughout

the implantation time is indicative of negative compatibility or even toxic effect

induced by the device leading to unsatisfactory overall biocompatibility.

13,39

A

stable large PMN population over extended periods of time suggests a continued

cellular migration from the vascular system since the lifetime of the PMN is

relatively short (48 hours) leading to an unresolved inflammatory phase, a sign

of poor biocompatibility of the BioMEMS.

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